Mutations in the tyrosine phosphatase CD45 gene in a child with severe combined immunodeficiency disease

Kung, Chun; Pingel, Jeanette T.; Heikinheimo, Markku; Klemola, Timo; Varkila, K; Yoo, Lina I.; Vuopala, Katri; Pöyhönen, Minna; Uhari, Matti; Rogers, Martin; Speck, Samuel H.; Chatila, Talal A.; Thomas, Matthew L.

doi:10.1038/73208

Cited by 279 publications

(167 citation statements)

References 15 publications

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“…No examples of the 6-bp deletion were detected, suggesting that 1168 -1173del is not a common genetic polymorphism. Very recently, another SCID patient lacking CD45 expression has been reported (27). This patient, similar to the case described here, was also presented at 2 mo of age and had greatly reduced numbers of peripheral T cells.…”

Section: Discussionsupporting

confidence: 54%

“…Recently, a second SCID patient lacking surface CD45 expression has been investigated, and the genetic lesions in the CD45 gene identified (27). Here we show that the patient described by Cale et al (26) has a homozygous 6-bp deletion in the CD45 gene, which results in a loss of glutamic acid 339 and tyrosine 340 in the first fibronectin type III module of the extracellular domain of CD45 and is responsible for the lack of cell surface expression of CD45.…”

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confidence: 70%

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A Deletion in the Gene Encoding the CD45 Antigen in a Patient with SCID

Tchilian

Wallace

Wells

et al. 2001

The Journal of Immunology

160

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SCID is a heterogeneous group of hereditary diseases. Mutations in the common γ-chain (γc) of cytokine receptors, including those for IL-2, IL-4, IL-7, IL-9, and IL-15, are responsible for an X-linked form of the disease, while mutations of several other genes, including Janus-associated kinase-3, may cause autosomal recessive forms of SCID. We investigated the first SCID patient to be described with minimal cell surface expression of the leukocyte common (CD45) Ag. CD45 is an abundant transmembrane tyrosine phosphatase, expressed on all leukocytes, and is required for efficient lymphocyte signaling. CD45-deficient mice are severely immunodeficient and have very few peripheral T lymphocytes. We report here that a homozygous 6-bp deletion in the gene encoding CD45 (PTPRC, gene map locus 1q31–32), which results in a loss of glutamic acid 339 and tyrosine 340 in the first fibronectin type III module of the extracellular domain of CD45, is associated with failure of surface expression of CD45 and SCID. Molecular modeling suggests that tyrosine 340 is crucial for the structural integrity of CD45 protein. This is the second description of a clinically relevant CD45 mutation, provides direct evidence for the importance of CD45 in immune function in humans, and suggests that abnormalities in CD45 expression are a possible cause of SCID in humans.

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Section: Discussionsupporting

confidence: 54%

mentioning

confidence: 70%

A Deletion in the Gene Encoding the CD45 Antigen in a Patient with SCID

Tchilian

Wallace

Wells

et al. 2001

The Journal of Immunology

160

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“…Nevertheless, the expression of these molecules in lymphocytes is essential for the normal function of the immune system. Thus, for example, in humans the failure to express CD45 results in a life-threatening immunodeficiency (40). These observations do not necessarily imply that the molecules carry out the same immunological functions in the lamprey lymphocyte-like cells as they do in mammalian lymphocytes.…”

Section: Discussionmentioning

confidence: 62%

Lamprey lymphocyte-like cells express homologs of genes involved in immunologically relevant activities of mammalian lymphocytes

Uinuk-ool

Mayer

Sato

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

130

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“…Experiments using CD45-deficient cell lines and animals indicate that CD45 ultimately has a positive effect on T cell activation (1). In CD45-deficient mice and humans, there is a profound block in thymic development demonstrating the importance of CD45 in promoting T cell activation and development (2)(3)(4)(5). The defects in T cell activation seen in the absence of CD45 are thought to be secondary to decreased activity of the Src family kinase Lck (and perhaps Fyn).…”

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confidence: 99%

Changes in the Role of the CD45 Protein Tyrosine Phosphatase in Regulating Lck Tyrosine Phosphorylation during Thymic Development

Falahati

Leitenberg

2007

The Journal of Immunology

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CD45-dependent dephosphorylation of the negative regulatory C-terminal tyrosine of the Src family kinase Lck, promotes efficient TCR signal transduction. However, despite the role of CD45 in positively regulating Lck activity, the distinct phenotypes of CD45 and Lck/Fyn-deficient mice suggest that the role of CD45 in promoting Lck activity may be differentially regulated during thymocyte development. In this study, we have found that the C-terminal tyrosine of Lck (Y505) is markedly hyperphosphorylated in total thymocytes from CD45-deficient mice compared with control animals. In contrast, regulation of the Lck Y505 phosphorylation in purified, double-negative thymocytes is relatively unaffected in CD45-deficient cells. These changes in the role of CD45 in regulating Lck phosphorylation during thymocyte development correlate with changes in coreceptor expression and the presence of coreceptor-associated Lck. Biochemical analysis of coreceptor-associated and nonassociated Lck in thymocytes, and in cell lines varying in CD4 and CD45 expression, indicate that CD45-dependent regulation of Lck Y505 phosphorylation is most evident within the fraction of Lck that is coreceptor associated. In contrast, Lck Y505 phosphorylation that is not coreceptor associated is less affected by the absence of CD45. These data define distinct pools of Lck that are differentially regulated by CD45 during T cell development.

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Mutations in the tyrosine phosphatase CD45 gene in a child with severe combined immunodeficiency disease

Cited by 279 publications

References 15 publications

A Deletion in the Gene Encoding the CD45 Antigen in a Patient with SCID

A Deletion in the Gene Encoding the CD45 Antigen in a Patient with SCID

Lamprey lymphocyte-like cells express homologs of genes involved in immunologically relevant activities of mammalian lymphocytes

Changes in the Role of the CD45 Protein Tyrosine Phosphatase in Regulating Lck Tyrosine Phosphorylation during Thymic Development

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